The house mouse (Mus musculus) is the foremost mammalian model system for understanding genetic variation in complex phenotypes. Body size has been especially well studied because of its central biological role and pervasive correlations with morphological, physiological and life-history traits, including human diseases such as obesity and cancer. Although the genetics of body size variation has been mostly studied in classical inbred strains, wild house mice also show substantial variation in body size across a wide range of habitats. A particularly dramatic example comes from mice on islands, which are usually much larger or smaller than their mainland counterparts. This phenomenon (termed the island syndrome) is observed across a diversity of mammals, raising the possibility of a general mechanism. The house mouse offers a powerful combination of genetic tools and natural variation, making it an excellent system for understanding the island syndrome. The proposed research will use a wild population of house mice from Gough Island that has experienced an especially dramatic (approximately twofold), rapid, and recent increase in body size to dissect the genetics of body size evolution on islands, with three aims. First, the colonization history of Gough Island mice will be reconstructed from genomic patterns of microsatellite variation using an approximate Bayesian approach. Second, mice from Gough Island and a closely related population will be bred in a common environment to confirm that body size differences have a genetic component. Third, genomic regions responsible for the rapid evolution of body size in mice from Gough Island will be identified using quantitative trait locus mapping. This research will provide some of the first genetic insights into a commonly observed evolutionary pattern and help connect the genetics of size variation in wild mice to that in laboratory mice and humans. Relevance: This study is relevant to public health because it will advance our understanding of the genetic basis of body size variation in a biomedical model organism and provide candidate genomic regions for size-related diseases, such as obesity and cancer, in humans.